IL-2 inducible T-cell kinase (abbreviated as Itk hereinafter) is a non-receptor tyrosine kinase classified in the Tec kinase family. Itk is known to be expressed in T-cells, natural killer (NK) cells and mast cells. Itk plays an essential role in T-cell differentiation, proliferation and migration, and the production of cytokines such as IL-2, IL-4, IL-5, IL-10 and IL-13 (see, Nature Immunology vol. 2, no. 12, 1183-1188, (2001)). T-cells are activated with antigen presentation to the T-cell receptor (TCR) by the antigen presenting cells. Subsequently, a cascade of T-cell signal transduction initiates to activate Lck, Itk, NFAT etc., and leads to cytokine production (see, Trends in Immunology, vol. 24, no. 5, 249-253, (2003)). It suggests the inhibition of Itk relates to therapy of T-cell mediated diseases.
For example, it was reported that Itk knockout mice showed the reduction of production of cytokines IL-2, IL-4, IL-5, IL-10 and IFN-γ compared to the wild type (see, Nature Immunology vol. 2, no. 12, 1183-1188, (2001)) and the reduction of lung inflammation on allergen challenge with ovalbumin (see, Journal of Immunology vol. 170, 5056-5063, 2003). In addition, Itk gene is highly expressed in peripheral blood T cells from patients with atopic dermatitis (see, International Archives of Allergy and Immunology, vol. 129, No. 4, 327-340, 2002). Recently, it was suggested that inhibition of Itk blocks HIV infection by affecting multiple steps of HIV replication (see, Proceedings of the National Academy of Sciences U.S.A., vol. 105, 6684-6689, 2008). Therefore, the compounds having Itk inhibitory activity are possible remedies for allergic asthma, atopic dermatitis, HIV infection, other T-cell mediated diseases and so on.
As prior arts regarding the present invention, the following patent applications are exemplified.
It has been disclosed that a bis-aryl amide derivative represented by formula (A)
wherein, R1A is an aryl ring system or a 5-14 membered nitrogen containing heteroaryl or heterocyclic ring system; any of which may be optionally independently substituted with 1 to of 4 ZA groups; R2A is
R3A is hydrogen or alkyl substituted with one or more ZA groups; RbA is independently H, C1-6 alkyl, C6-10 aryl and so on, any of which may be optionally substituted with one or more ZA groups; RcA is independently H, halo, hydroxyl, C1-6 alkyl and so on; ZA is an optional substituent independently selected at each occurrence froma*) halo, nitrile, hydroxyl, alkoxy, aryloxy and so on; or b*) alkyl, alkenyl, aryl, heteroaryl, and so on, any of which may be optionally substituted with one or more of the substituents listed in the above section a*; and nA is an integer from 0 to 3 (the definition of each group in the above described formula is excerpted), is useful for c-Met kinase inhibitor (From WO 2008/086014).
Furthermore, it has been described that an aminopyrazine compound represented by formula (B)
wherein R1B is a 5-6 membered monocyclic aryl or heteroaryl ring; R1B is optionally substituted with 1-5 J1B groups; C2B, C3B and C5B are carbon; R2B is -QB or -QB-Q1B; QB is a 3-7 membered monocyclic saturated or unsaturated non-aromatic ring; Q1B is a 3-8 membered monocyclic saturated or unsaturated ring; JB is fluoro, oxo, or a moiety containing a hydrogen bond acceptor; LB is —C(O)—NH— or —C(O)N(C1-6 alkyl)-; nB is 0 or 1 (the definition of each group in the above described formula is excerpted), is useful for ATR kinase inhibitor (From WO 2010/054398).
In addition, it has been disclosed that an aminopyrazine compound represented by formula (C)
wherein YC is a C 1-10 aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with O, S, C(O) and so on; ring AC is a 5 membered heteroaryl ring; QC is a 5-6 membered monocyclic aromatic ring or an 8-10 membered bicyclic aromatic ring; R5C is H, 3-7 membered monocyclic fully saturated, partially unsaturated ring, or aromatic ring; an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring; LC is a C1-4 alkyl chain wherein up to two methylene units of the alkyl chain are optionally replaced with O, S, —C(O)—, and so on; R1C is H or C1-6 alkyl; R2C is H, C1-6 alkyl, a 4-8 membered cyclic ring and so on; or R1C and R2C, taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring; J2C is halo, CN, a 5-6 membered aromatic or nonaromatic monocyclic ring, and so on; mC is 0 or 1; qC is 0, 1, or 2; pC is 0 or 1 (the definition of each group in the above described formula is excerpted), is useful for ATR kinase inhibitor (From WO2010/071837).
Additionally, it has been disclosed that an aminopyridine compound represented by formula (D)
wherein T1D is aromatic heterocyclic, aromatic heterobicyclic, phenyl, naphthyl, or indenyl, wherein T1D is optionally substituted with one or more R1D; T2D is aromatic heterocyclic, aromatic heterobicyclic, phenyl, naphthyl, or indenyl, wherein T2D is optionally substituted with one or more R2D; R1D, R2D are independently selected from the group consisting of T3D, C1-6 alkyl, halogen, CN, and so on; T3D is C3-7 cycloalkyl, heterocyclic, or phenyl (the definition of each group in the above described formula is excerpted), is useful for Itk kinase inhibitor (From WO2008/025820).
Meanwhile, some protein kinases, such as Lck, activate Itk. In addition, it is known that retinal abnormalities are observed in Lck (the Src family of non receptor-type kinases) deficient mice (See oncogene, 16, 2351-2356, (1998)). Therefore, it is important to express selectivity for Itk over Lck in developing Itk inhibitor as pharmaceutical product.